Project 3 Project Summary Bone Marrow Transplant (BMT) has improved outcomes for patients with high risk or relapsed acute myeloid leukemia (AML) and Myelodysplastic Syndrome (MDS). This is due to both the ability to give high doses of chemotherapy and/or radiation to further eradicate residual leukemia and because the donor cells may detect and lyse residual tumor cells, termed the graft-versus-leukemia (GVL) effect. However, patients with high risk or persistent disease continue to experience a dismal prognosis despite BMT, ranging from 10-40% survival at 5 years. Thus, developing novel therapeutics for myeloid malignancies is critical. T-cell immunotherapy post BMT using virus-specific cytotoxic T lymphocytes, has been highly successful for the treatment of virus- associated diseases (including EBV+ lymphomas) after BMT. However, only limited studies have been conducted utilizing T-cell therapies targeting non-viral tumor-associated antigens for patients after BMT. The development of T-cells expressing a chimeric antigen receptor (CAR) for CD19 has shown significant promise for patients with B-cell acute lymphoblastic leukemia (ALL). However, greater than 40% of the responses are not durable because the tumor evades the immune system by downregulating or modulating expressed target antigens. Furthermore, this approach can only target tumor antigens expressed on the cell surface and many tumor-associated antigens (TAAs) are intracellular. Furthermore, to date, CAR-T-cell therapy has not been as successful clinically for patients with myeloid malignancies as CD19-CAR T cells have been for patients with ALL. To extend T cell therapy to patients with AML/MDS post allogeneic BMT, we have developed a novel strategy to reactivate and expand T cells with specificity for multiple TAAs: Survivin, PRAME and WT1, which collectively are expressed by >90% of myeloid blasts. We reason that targeting multiple TAAs simultaneously will minimize tumor immune escape. Interest in BMT is also building as a potential means to clear HIV-1- infected cells from infected persons and achieve a functional cure of HIV infection. However, interruption of ART post-transplant is associated with life-threatening HIV rebound. Therefore, we propose that reconstitution of the immune system early post-BMT with the adoptive transfer of ex vivo expanded TAA and HIV-specific T cells carrying the CCR5?32 mutation would confer protection from relapse AND could reconstitute an effective HIV cellular immune response to prevent such uncontrolled rebound. Our central hypotheses are: (i) that the GVL effect post BMT will be enhanced by adoptive transfer of T-cells targeting multiple TAAs and (ii) that this approach can be applied to HIV-associated malignancies and will be effective for targeting multiple HIV and tumor associated antigens. We will test these hypotheses in clinical trials proposed for Aim 1. In we will generate and infuse T-cell products from eligible BMT donors that target multiple TAAs (+/- HIV) to HIV+ and HIVneg patients with AML/MDS. In Aim 2 we will evaluate the anti tumor and antiviral clinical and immune responses after T cell infusion. In summary, this approach may enable T-cell immunotherapy to become more broadly applied to all patients with malignancies after BMT.